Bayesian modeling of skewed X inactivation in genetically diverse mice identifies a novel Xce allele associated with copy number changes

Abstract

Female mammals are functional mosaics of their parental X-linked gene expression due to X chromosome inactivation (XCI). This process inactivates one copy of the X chromosome in each cell during embryogenesis and that state is maintained clonally through mitosis. In mice, the choice of which parental X chromosome remains active is determined by the X chromosome controlling element (Xce), which has been mapped to a 176 kb candidate interval. A series of functional Xce alleles has been characterized or inferred for classical inbred strains based on biased, or skewed, inactivation of the parental X chromosomes in crosses between strains. To further explore the function-structure basis and location of the Xce, we measured allele-specific expression of X-linked genes in a large population of F1 females generated from Collaborative Cross strains. Using published sequence data and applying a Bayesian “Pólya urn” model of XCI skew, we report two major findings. First, inter-individual variability in XCI suggests mouse epiblasts contain on average 20-30 cells contributing to brain. Second, NOD/ShiLtJ has a novel and unique functional allele, Xcef, that is the weakest in the Xce allelic series. Despite phylogenetic analysis confirming that NOD/ShiLtJ carries a haplotype almost identical to the well-characterized C57BL/6J (Xceb), we observed unexpected patterns of XCI skewing in females carrying the NOD/ShiLtJ haplotype within the Xce. Copy number variation is common at the Xce locus and we conclude that the observed allelic series is a product of independent and recurring duplications shared between weak Xce alleles.

Mechanisms of Choice in X-Chromosome Inactivation

“…Overall, six competing Xce alleles have been proposed, with the order of strength being a < f < e < b < c < d, where Xce a is the most likely to be inactivated and Xce d the least likely. A new study has identified an additional allele, reportedly the weakest in the Xce allelic series [145]. In Xce heterozygotes, the X chromosome carrying the weaker of the two alleles is more likely to be inactivated.…”

Which mouse multiparental population is right for your study? The Collaborative Cross inbred strains, their F1 hybrids, or the Diversity Outbred population

“…Furthermore, the CC-RIX can be used to detect parent-of-origin effects using reciprocal F1 designs (Oreper et al . 2018; Sun et al . 2021), though we do not investigate these approaches here.…”

“…The complex population structure of the CC-RIX reduces mapping power, but does enable more accurate estimation of additive heritability. Furthermore, the CC-RIX can be used to detect parent-of-origin effects using reciprocal F1 designs (Oreper et al 2018; Sun et al 2021), though we do not investigate these approaches here. These key principles should also extend to MPPs (and more broadly any mapping population) of other organisms with similar experimental features ( e.g.…”

“…2011; Schoenrock et al . 2018; Sun et al . 2021), and the Diversity Outbred (DO) population (Churchill et al .…”

Mechanisms of Choice in X-Chromosome Inactivation

“…Overall, six competing Xce alleles have been proposed, with the order of strength being a<f<e<b<c<d, where Xce a is the most likely to be inactivated and Xce d the least likely. A new study has identified an additional allele, reportedly the weakest in the Xce allelic series (Sun et al, 2021). In Xce heterozygotes, the X chromosome carrying the weaker of the two alleles is more likely to be inactivated.…”